Light-driven activation: Developing photoremovable protecting groups for synthesis and biomedical applications
Date
2024-08
Authors
Dissanayake, Komadhie
Major Professor
Advisor
Winter, Arthur H
Kraus, George
Smith, Emily
Stanley, Levi
Li, Junqi
Committee Member
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Abstract
This dissertation encompasses an interdisciplinary exploration of Photo-removable
protecting groups (PPGs), which includes identifying novel PPGs, performance optimization of
existing PPGs and demonstration of their applications. The research delves into the design and
optimization of PPGs for biomedical fields, emphasizing the importance of tailored structural
features for optimal function within biological environments. Especially, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-based PPGs were refined to improve the efficiency of
photorelease in the NIR (Near Infra-Red) region addressing a critical shortcoming of previously
reported NIR absorbing BODIPY-based PPGs. This was achieved via structure rigidification and
trapping the intermediate cation, resulting in a maximum of ~50-fold improvement in quantum
yield of release (Φr) than the previous BODIPY-based similar PPGs. Complementing these
efforts, structure-photoreactivity studies aimed at enhancing the deprotection efficiency of
BODIPY-based PPGs provide profound insights into the correlation between substituted
functional groups and Φr. Both Electron-donating groups (EDG) and electron-withdrawing
groups (EWG) were used to assess the effect on Φr when substituted at the boron and 2-core
positions. While EDGs improved the Φr, EWGs had the opposite effect. Additionally, the
substitution at the meso methyl position by aryl groups unexpectedly lowered the Φr indicating
the presence of competing photophysical/photochemical pathways. Furthermore, in this
dissertation strategic design initiatives targeting a pyridinium-based zwitterionic PPG for
biological applications are discussed. This zwitterionic PPG showed excellent water solubility
and a great release efficiency at biological pH compared to similar-sized PPGs, showcasing its
potential applications in light-triggered biomolecule activity modulation. Finally, the dissertation
highlights a proof of principle study demonstrating the applicability of BODIPY-based PPGs in
glycan synthesis, broadening their utility beyond the most studied biological applications. This
study showed a synthesis of trisaccharide with an impressive 70% yield with just one
purification. Collectively, these findings underscore the interdisciplinary nature of the research,
demonstrating PPGs’ potential to be used in biology and synthetic chemistry.
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article